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Frankó, A. ; Irmler, M. ; Prehn, C. ; Heinzmann, S.S. ; Schmitt-Kopplin, P. ; Adamski, J. ; Beckers, J. ; von Kleist-Retzow, J.C.* ; Wiesner, R.* ; Häring, H.-U. ; Heni, M. ; Birkenfeld, A.L. ; Hrabě de Angelis, M.

Bezafibrate reduces elevated hepatic fumarate in insulin-deficient mice.

Biomedicines 10:616 (2022)
Publ. Version/Full Text Research data DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
Glucotoxic metabolites and pathways play a crucial role in diabetic complications, and new treatment options which improve glucotoxicity are highly warranted. In this study, we analyzed bezafibrate (BEZ) treated, streptozotocin (STZ) injected mice, which showed an improved glucose metabolism compared to untreated STZ animals. In order to identify key molecules and pathways which participate in the beneficial effects of BEZ, we studied plasma, skeletal muscle, white adipose tissue (WAT) and liver samples using non-targeted metabolomics (NMR spectroscopy), targeted metabolomics (mass spectrometry), microarrays and mitochondrial enzyme activity measurements, with a particular focus on the liver. The analysis of muscle and WAT demonstrated that STZ treatment elevated inflammatory pathways and reduced insulin signaling and lipid pathways, whereas BEZ decreased inflammatory pathways and increased insulin signaling and lipid pathways, which can partly explain the beneficial effects of BEZ on glucose metabolism. Furthermore, lysophosphatidylcholine levels were lower in the liver and skeletal muscle of STZ mice, which were reverted in BEZ-treated animals. BEZ also improved circulating and hepatic glucose levels as well as lipid profiles. In the liver, BEZ treatment reduced elevated fumarate levels in STZ mice, which was probably due to a decreased expression of urea cycle genes. Since fumarate has been shown to participate in glucotoxic pathways, our data suggests that BEZ treatment attenuates the urea cycle in the liver, decreases fumarate levels and, in turn, ameliorates glucotoxicity and reduces insulin resistance in STZ mice.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Bezafibrate ; Diabetes ; Fumarate ; Insulin Resistance ; Lysophosphatidylcholine
ISSN (print) / ISBN 2227-9059
e-ISSN 2227-9059
Journal Biomedicines
Quellenangaben Volume: 10, Issue: 3, Pages: , Article Number: 616 Supplement: ,
Publisher MDPI
Publishing Place Basel, Switzerland
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Experimental Genetics (IEG)
Institute of Diabetes Research and Metabolic Diseases (IDM)
CF Metabolomics & Proteomics (CF-MPC)
Research Unit Analytical BioGeoChemistry (BGC)
Grants German Center for Diabetes Research